Translating cellular immunotherapies for autoimmunity to canine clinical trials

将自身免疫细胞免疫疗法转化为犬类临床试验

基本信息

  • 批准号:
    10454148
  • 负责人:
  • 金额:
    $ 82.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Project summary: Autoimmunity occurs when the body's immune system mistakenly attacks normal tissues, leading to disease. Treatments for autoimmunity chronically suppress the immune system, which risks fatal infection; thus the ideal therapy would eliminate only the disease-causing autoimmune cells while preserving normal immunity. We recently developed a novel gene-engineered chimeric autoantibody receptor T cell (CAAR-T) therapy that uses the autoantigen targeted in disease to direct T cell cytotoxicity against only those B cells that express autoantigen-specific B cell receptors (BCRs). We have shown that CAAR-Ts cause complete histologic and serologic remission of autoantibody (autoAb)-mediated disease in an experimental mouse model and engraft to form memory CAAR-Ts that can provide lasting protection against disease recurrence. In considering how to translate CAAR-T technology to first-in-human trials, a challenge arises given that most autoimmune patients do not face imminent death from their disease, unlike the first cancer patients treated with gene-engineered cellular therapies. The current preclinical pipeline relies on mice whose disease is artificially induced and treated shortly after disease induction. Cytokine release syndrome does not occur in mice despite being one of the most common toxicities in cancer patients. The field has not pursued better preclinical models given the risks of time and money involved in experimenting in a new animal species. Given the curative potential for CAAR-T in autoimmunity and the increasing interest in developing cellular therapies for non-oncologic indications, we believe it is now crucial to establish a higher preclinical standard. We thus seek to establish dogs with naturally occurring autoimmune disease as an ideal preclinical system for assessing cellular immunotherapies, which we believe will better predict the safety and efficacy of human therapies than experimental mouse models. This proposal meets the high-risk, high-reward nature of the transformative R01 program, as gene-engineered cellular therapies have never been tested in any naturally occurring autoimmune disease. The successful treatment of autoimmunity in dogs with CAAR-T would not only be a breakthrough in veterinary medicine, but would also establish dogs as an ideal species for preclinical validation of human cellular immunotherapies and provide compelling evidence for doctors and patients to enroll for future CAAR-T first-in-human trials. Ultimately, our work could facilitate the translation of cellular immunotherapies for a broad range of canine and human diseases.
项目总结: 当身体的免疫系统错误地攻击正常组织,导致疾病时,就会发生自身免疫。 自身免疫的治疗长期抑制免疫系统,有致命感染的风险;因此 理想的治疗方法是只清除致病的自身免疫细胞,同时保持正常的免疫力。 我们最近开发了一种新的基因工程嵌合自身抗体受体T细胞(CAAR-T)疗法, 使用针对疾病的自身抗原来引导T细胞对仅表达表达的B细胞的杀伤作用 自身抗原特异性B细胞受体(BCR)。我们已经证明CAAR-T会引起完整的组织学和 自身抗体(AutoAb)介导的小鼠实验性疾病的血清学缓解及其移植 形成记忆能力,对疾病复发提供持久的保护。在考虑如何 将CAAR-T技术转化为首个人体试验,这是一个挑战,因为大多数自身免疫患者 与第一批用基因工程治疗的癌症患者不同,他们不会面临迫在眉睫的死亡 细胞疗法。目前的临床前管道依赖于小鼠的疾病是人工诱导和 在疾病诱导后不久进行治疗。细胞因子释放综合征不会在小鼠身上发生,尽管它是 癌症患者最常见的毒性反应。该领域尚未寻求更好的临床前模型,因为 在一种新的动物物种上进行实验涉及时间和金钱的风险。考虑到治疗的潜力 CAAR-T在自身免疫中的作用及其在非肿瘤细胞治疗中的研究进展 适应症,我们认为现在至关重要的是建立一个更高的临床前标准。因此,我们寻求建立 用自然发生的自身免疫性疾病犬作为评估细胞的理想临床前系统 免疫疗法,我们认为这将更好地预测人类疗法的安全性和有效性,而不是 实验小鼠模型。此建议符合变革性R01的高风险、高回报特性 计划,因为基因工程细胞疗法从未在任何自然发生的自身免疫中进行过测试 疾病。CAAR-T对犬自身免疫的成功治疗不仅是对 兽医学,但也将使狗成为人类临床前验证的理想物种 细胞免疫疗法,为医生和患者登记参加未来的CAAR-T提供了令人信服的证据 第一次人体试验。最终,我们的工作可以促进广泛的细胞免疫疗法的翻译 一系列犬类和人类疾病。

项目成果

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NICOLA J MASON其他文献

NICOLA J MASON的其他文献

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{{ truncateString('NICOLA J MASON', 18)}}的其他基金

Translating cellular immunotherapies for autoimmunity to canine clinical trials
将自身免疫细胞免疫疗法转化为犬类临床试验
  • 批准号:
    9982789
  • 财政年份:
    2018
  • 资助金额:
    $ 82.75万
  • 项目类别:
Translating cellular immunotherapies for autoimmunity to canine clinical trials
将自身免疫细胞免疫疗法转化为犬类临床试验
  • 批准号:
    10229583
  • 财政年份:
    2018
  • 资助金额:
    $ 82.75万
  • 项目类别:
Identification of a naturally occurring model for EBV-associated lymphomagenesis
EBV 相关淋巴瘤发生的自然模型的鉴定
  • 批准号:
    8424215
  • 财政年份:
    2012
  • 资助金额:
    $ 82.75万
  • 项目类别:
Identification of a naturally occurring model for EBV-associated lymphomagenesis
EBV 相关淋巴瘤发生的自然模型的鉴定
  • 批准号:
    8244208
  • 财政年份:
    2012
  • 资助金额:
    $ 82.75万
  • 项目类别:
C-Rel in resistance to toxoplasma gondii
C-Rel 抵抗弓形虫
  • 批准号:
    6424576
  • 财政年份:
    2002
  • 资助金额:
    $ 82.75万
  • 项目类别:
C-Rel in resistance to toxoplasma gondii
C-Rel 抵抗弓形虫
  • 批准号:
    6775695
  • 财政年份:
    2002
  • 资助金额:
    $ 82.75万
  • 项目类别:
C-Rel in resistance to toxoplasma gondii
C-Rel 抵抗弓形虫
  • 批准号:
    6653057
  • 财政年份:
    2002
  • 资助金额:
    $ 82.75万
  • 项目类别:
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